Alzheimer’s disease (AD) is a degenerative disorder characterized by cognitive dysfunction and BDNF/TrkB is a well-conceived anti-AD signaling. Cynomorium songaricum Rupr. (C. songaricum) is a herb with promising neuroprotective effects and the function is majorly attributed to flavonoids. The current study attempted to explore the effects of total flavonoids of C. songaricum (CS) on AD model by focusing on changes in BDNF/TrkB axis. AD model was induced in rats via transcranial injection of Aβ1-42 and AD symptoms treated with CS of three doses. Donepezil was used as the positive control. Changes in rat memory and learning abilities, brain histological, apoptosis, production of neurotransmitters, BDNF/TrkB axis, and apoptosis-related markers were measured. The injection of Aβ1-42 induced cognitive dysfunction in AD rats. The integrity of brain tissue structure was destructed and apoptosis was induced in AD rats, in which was found the increased production of AChE and Aβ1-42, and decreased production of ChAT, ACH. At the molecular level, the expression of BDNF, TrkB, and Bcl-2 was suppressed, while the expression of Bax, caspase-3, and caspase-9 was induced. After the administration of CS, the memory and learning abilities of rats were improved, the production of neurotransmitter was restored, ordered arrangement of pyramidal cells was retained, and neuron apoptosis was inhibited. The attenuation of Aβ1-42-indcued impairments was associated with the activation of BDNF/TrkB axis and blockade of apoptosis-related pathways. Collectively, CS can improve learning and memory abilities in Aβ1-42-induced AD model rats. which may depend on the activation of the hippocampal BDNF/TrkB signaling pathway.